Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Neuropathol Exp Neurol. 2010 Aug;69(8):777-88. doi: 10.1097/NEN.0b013e3181e77ed9.
Cerebral accumulation of amyloid-beta (Abeta) is characteristic of Alzheimer disease and of amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy of CI-1011, an inhibitor of acyl-coenzyme A:cholesterol acyltransferase, which is suitable for clinical use, in reducing amyloid pathology in both young (6.5 months old) and aged (16 months old) human APP transgenic mice. Treatment of young animals with CI-1011 decreased amyloid plaque load in the cortex and hippocampus and reduced the levels of insoluble Abeta40 and Abeta42 and C-terminal fragments of APP in brain extracts. In aged mice, CI-1011 specifically reduced diffuse amyloid plaques with a minor effect on thioflavin S-positive dense-core plaques. Reduced diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in human APP mice by limiting generation and increasing clearance of diffusible Abeta.
淀粉样蛋白-β（Abeta）在大脑中的积累是阿尔茨海默病和淀粉样前体蛋白（APP）转基因小鼠的特征。在这里，我们评估了酰基辅酶 A：胆固醇酰基转移酶抑制剂 CI-1011 的疗效，CI-1011 适合临床使用，可降低年轻（6.5 个月大）和老年（16 个月大）人类 APP 转基因小鼠的淀粉样蛋白病理学。CI-1011 治疗年轻动物可降低皮质和海马体中的淀粉样斑块负荷，并降低脑提取物中不溶性 Abeta40 和 Abeta42 以及 APP C 端片段的水平。在老年小鼠中，CI-1011 特异性减少弥散性淀粉样斑块，对硫黄素 S 阳性致密核心斑块的影响较小。可扩散淀粉样蛋白的减少伴随着星形胶质细胞增生的抑制和小胶质细胞激活的增强。总的来说，这些数据表明，CI-1011 通过限制可扩散 Abeta 的产生和增加其清除来减少人类 APP 小鼠中的淀粉样蛋白负担。
